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Acquired Chromosome 11q Deletion Involving the Ataxia Teleangiectasia Locus in B-Cell Non-Hodgkin’s Lymphoma: Correlation With Clinicobiologic Features

From the Dipartimento di Scienze Biomediche e Terapie Avanzate, Sezione di Ematologia, and Dipartimento di Medicina Sperimentale e Diagnostica, Sezione di Microbiologia, University of Ferrara, Ferrara, and Istituto Dermopatico dell’Immacolata, IRCCS, Roma, Italy.

Address reprint requests to Antonio Cuneo, MD, Dipartimento di Scienze Biomediche, Sezione di Ematologia Università di Ferrara, Via Savonarola, 9 - 44100 Ferrara, Italy; email sse{at}dns.unife.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To study the clinicobiologic significance of acquired 11q deletions involving the ataxia teleangiectasia locus (ATM+/-) in B-cell non-Hodgkin’s lymphomas (NHL).

PATIENTS AND METHODS: Fifty-three indolent lymphomas and 82 aggressive lymphomas were studied by conventional cytogenetic analysis and by fluorescence in situ hybridization using an 11q22–23 probe recognizing ATM sequences. Pertinent clinical data were collected.

RESULTS: A hemizygous ATM deletion was seen in 44% to 88% of the interphase cells in 15 cases (11.1%); four patients had an indolent lymphoma (follicular center cell lymphoma), and 11 patients had an aggressive lymphoma (five mantle-cell lymphomas [MCLs] and six diffuse large-cell lymphomas). Dual-color hybridization studies showed ATM deletion to be possibly a secondary aberration in three patients with MCL. Ten out of 15 ATM+/- patients had a complex karyotype, 11 out of 15 had more than 90% abnormal metaphases (AA karyotype status), and +12, 13q14 deletion, and 17p13 deletion were seen in seven, four, and five cases, respectively. Patients with ATM+/- more frequently had a complex karyotype (P = .01) and the AA karyotype (P = .04) compared with patients without ATM+/-. With the exception of a poor performance status (P = .001), no correlation was found between ATM+/-, initial clinical variables, and complete remission rate; whereas a highly significant association was found with shorter survival (P < .0001). This cytogenetic lesion maintained its prognostic importance in multivariate analysis (P = .0004), along with performance status (P = .0006), serum lactate dehydrogenase level (P = .03), splenomegaly (P = .01), and histologic grade (P = .03). When analyzing indolent lymphomas and aggressive lymphomas separately, ATM+/- maintained its prognostic importance as an independent variable in both histologic groups (P = .0001 and P = .016, respectively).

CONCLUSION: Though possibly not representing a primary genetic lesion in the majority of cases, the acquired ATM+/- status has clinicobiologic importance in NHL, possibly representing a major cytogenetic determinant of outcome.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CHROMOSOME 11q deletions were shown to occur in B-cell lymphoid neoplasias (including non-Hodgkin’s lymphoma [NHL]) predominantly of low to intermediate grade¹ and chronic lymphocytic leukemia, where they have been associated with a distinct disease subset.² Subsequent deletion mapping studies demonstrated that the commonly deleted region in these disorders consisted of a 2- to 3-megabasepair DNA segment at the 11q22.3-23.1 bands,³ where the ataxia teleangiectasia mutated (ATM) gene is located. Ataxia teleangiectasia (AT) is an autosomal recessive multisystem disorder that derives from the inheritance of a structurally abnormal ATM gene.⁴ The ATM gene protein product is probably involved in signaling apoptosis in response to DNA damage⁵ and, not surprisingly, AT subjects have chromosomal instability and a strong predisposition to develop lymphoid tumors, especially, but not exclusively, T-cell prolymphocytic leukemia (T-PLL).^6,7 The link between 11q deletions involving the ATM locus and lymphomagenesis was recently reinforced by the demonstration that (1) 11q22-23 deletion is frequently found in B-cell tumors, especially in B-cell chronic lymphocytic leukemia (B-CLL),² where it denotes a relatively aggressive disease having karyotype instability^2,8; (2) acquired missense ATM gene mutations are associated with deletion of the remaining allele in sporadic T-PLL⁹; and (3) 11q deletion with inactivation of the remaining ATM allele may occur in B-CLL and in B-cell lymphomas, including mantle-cell lymphoma (MCL).^9-11

To analyze the relationship between 11q deletions determining monoallelic loss of the ATM locus (ATM+/-) and B-cell NHL, this cytogenetic and fluorescence in situ hybridization (FISH) study was performed, with the following end points: (1) to ascertain the frequency and distribution of the ATM+/- status in various histologic subtypes of NHL, (2) to establish whether this deletion is an early event or a secondary aberration in the history of NHL, (3) to analyze its correlation with cytogenetic features, and (5) to disclose possible clinical correlations for this genetic lesion.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients and Clinical Parameters
Inclusion criteria included the following: histologic diagnosis of B-cell NHL, successful chromosome analysis, availability of cytogenetic pellet for interphase cytogenetic analysis, and adequate clinical information on presentation features and outcome. One hundred thirty-five patients with NHL who met the above criteria were seen at the Institute of Hematology, University of Ferrara, Ferrara, Italy, in a 10-year period; these patients form the basis of the present report. The histologic diagnoses were made, according to the Revised European-American Lymphoma classification,¹² on lymph node material in 122 cases or on surgically removed spleen in the remaining cases. To analyze the prognostic impact of the ATM+/- status, the patients were grouped into indolent lymphomas (including small lymphocytic lymphoma, marginal zone B-cell lymphoma, and follicular center cell lymphoma) and aggressive lymphomas (including MCL and diffuse large-cell lymphoma).¹³

Staging procedures in all patients included physical examination, a routine laboratory profile, a chest x-ray film, and abdomen ultrasonography. The vast majority of patients were also assessed by bone biopsy and computed tomography scan and, when indicated, by barium contrast radiography and/or gastroduodenal endoscopy. Not all patients underwent the same staging procedure because some investigations were felt to be redundant in some cases (some elderly patients were not assessed by computed tomography scan because adenopathy was demonstrated by ultrasonography examination, and some did not receive a trephine bone biopsy because prominent bone marrow [BM] involvement was present on a BM aspirate). Peripheral-blood involvement was studied by light microscopy examination of smears stained by the May-Grunwald-Giemsa method. Clinical records were surveyed for all cases.

Complete remission (CR) was defined as the resolution of all abnormal symptoms, signs, and imaging attributable to the lymphoma for at least 3 months after the completion of treatment.

The patients included in this analysis were treated according to the guidelines in use at our institution during the study period. In patients less than 70 years old, stage II to IV indolent lymphomas (small lymphocytic lymphoma, marginal zone B-cell lymphoma, and low- to intermediate-grade follicle center cell lymphoma) were treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen in all but five patients, who received regimens not containing anthracyclines. Radiotherapy was given in the majority of cases. Elderly patients and patients with limited disease were treated with the cyclophosphamide, vincristine and prednisone (CVP) regimen, with or without radiotherapy; four patients with small lymphocytic lymphoma were offered chlorambucil plus a corticosteroid drug as first-line therapy. Splenectomy was performed in four marginal zone B-cell lymphomas. MCLs were treated by the CHOP regimen plus radiotherapy. Patients less than 65 years old with large-cell lymphomas were treated with the methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) regimen, with or without radiotherapy. Six patients were treated by other anthracycline-containing schemes, whereas the CHOP regimen with adequate dose reduction depending on age and general conditions was offered to elderly patients.

Conventional Chromosome Analysis
Cytogenetic investigations were performed at diagnosis. Single-cell suspensions were prepared, as previously described,¹⁴ after collection of a portion of surgically removed lymph node or spleen. In nine cases with leukemic presentation, BM and PB samples were studied. The cells obtained from BM, lymph node, and spleen specimens were separated over a 1,077 density gradient. In all cases, cell suspensions containing more than 90% neoplastic cells were cultured for 24 to 72 hours, with and without the mitogens phorbol myristate acetate (50 ng/mL) and lipopolysaccharide from Escherichia coli (100 mg/mL). Whenever possible, 20 metaphases were studied; a complex karyotype was defined by the presence of more than five clonal abnormalities, and the AA karyotype status was defined by the presence of more than 90% abnormal metaphases in a given patient.

FISH
Experimental design. Cells for FISH studies were taken from the same diagnostic samples that were used for cytogenetic analysis. All 135 patients were screened for the presence of deletion of the ATM locus and for 13q14 deletion in interphase cells. The 13q14 probe was previously shown to detect a deletion in approximately 20% of NHL¹⁵ and was used in this study to analyze in parallel the relationship existing between ATM deletion or 13q14 deletion and cytogenetic features.

Because FISH is more sensitive than cytogenetic analysis, 15 patients having the ATM+/- status were better characterized using the p53 probe and a chromosome 12–specific probe, which were shown to detect a 17p deletion or trisomy 12 in a significant fraction of NHL.¹⁴

Finally, dual-color FISH, using a biotin-labeled ATM probe (signal amplification with green fluorescence) and a digoxigenin-labeled BCL1 probe (signal amplification with red fluorescence), was performed in four patients having ATM gene deletion and BCL1 rearrangement. These experiments were carried out to ascertain which lesion had occurred first in the abnormal clone, and we elected to use the BCL1 probe because it showed a high hybridization efficiency in our hands. To be able to compare the resulting hybridization pattern with that obtained in a disease having a demonstrated relationship with ATM deletion, we elected to study two cases of TCL1-rearranged T-PLL carrying ATM deletion, using a digoxigenin-labeled TCL1 probe and the biotin-labeled ATM probe.

Detection of ATM deletion. The FISH procedure for the detection of deletion at the ATM locus was as follows. The slides were incubated for 60 minutes with RNAse 100 µg/mL (Boehringer Mannheim, Rannheim, Germany), washed twice in two x standard saline citrate (SSC), dehydrated in ethanol alcohol series (75%, 85%, and 100%), and air-dried. The denaturation was performed by immersion of the slides in a 70% formamide/two x SSC solution at 70°C for 2 minutes and dehydrated in an ice-cold ethanol alcohol series (70%, 85%, and 100%). The lambda EMBL3 clones 19 and 65, spanning an area of approximately 40 kilobases within the middle portion of the ATM gene, were isolated as previously described¹⁶ and used to detect ATM gene deletion. The DNA probe was biotinylated with a BioNick Labelling System Kit (GIBCO BRL, Gaithersburg, MD) according to the manufacturer’s instructions and precipitated with Human Cot-1 DNA (GIBCO BRL) to suppress nonspecific signals caused by repetitive sequences. Two hundred ng of the DNA probe were resuspended in a hybridization mixture (240 µL, total volume) with 50% formamide, 10% dextran sulphate in 12.5 x standard saline citrate phosphate, and five x Denhard’s solution. The mixture (60 µL) was added to each slide and incubated overnight. Posthybridization washes included 50% formamide/two x SSC, one x SSC, and 0.1 x SSC baths at 45°C each, with intermittent agitation. Detection was performed with alternating layers of fluorescein isothiocyanate avidin and biotinylated goat anti-avidin (5 ng/µL; Vector Laboratories, Burlingame, CA) until two layers of avidin were applied; each treatment was followed by two x SSC washes for 2 minutes each. A 46'-diamidino-2-phenylindole fluorescent antifade solution was applied onto the slides as counterstain. The evaluation was performed on more than 200 interphase cells on a Nikon fluorescence-equipped microscope (Nikon Italia, Florence, Italy). Images for illustration purposes were captured using a charge-coupled camera device (Genevision; Nikon Italia). To prevent misinterpretation of data deriving from the presence of trisomy or monosomy 11 in interphase cells, all patients were studied by FISH using a chromosome 11–specific pericentromeric probe (Oncor, Gaithersburg, MD).

Hybridization of these ATM probes to five normal control samples was shown to produce two signals in more than 90% of cells, with less than 3% of cells having one signal (false deletion). The cutoff point for the recognition of ATM deletion was set at more than 10% interphase cells with one signal.

Other probes. 13q14 deletion was investigated using the C21 cosmid, recognizing DNA sequences telomeric of the Rb gene and centromeric to the D13S25 locus.¹⁷ The p53.3 cosmid recognizing p53 gene sequences at 17p13 was used to detect p53 deletion.¹⁴ A commercially available chromosome 12–specific probe (Oncor, Gaithersburg, MD) was used to detect trisomy 12. BCL1 involvement was documented using the yeast artificial chromosome probe 214D11, spanning a 390-kilobase region encompassing the major translocation cluster and the minor translocation clusters of the BCL1 locus at 11q13.¹⁷ The presence of three signals in interphase cells (one deriving from the normal allele and two deriving from the split BCL1 allele) was considered indicative of BCL1 involvement. TCL1 involvement was documented in two patients with inv(14)(q11q32) using the pPLC-1 and pPLC-4 cosmids, which flank the DNA region at 14q32 where the TCL1 breakpoints are known to occur, producing three signals in interphase cells in TCL1-rearranged cases. Conditions for slide pretreatment, hybridization, signal amplification, and visualization were as described above. The isolation and preparation of these probes and the conditions in use at our laboratories for their employment in FISH analysis was previously described in detail.^14,15,17,18 These probes were biotinylated (13q14, +12, and 17p13 probes) or digoxigenin-labeled (BCL1 and TCL1 probes) using commercial kits (GIBCO BRL, MD) and tested in five normal control samples. Less than 1% of cells showed three signals (false trisomy or false rearrangement), and less and than 5% of cells showed one signal (false deletion) with each probe. Therefore, the cutoff point for the recognition of trisomy and deletion was set at 2% and 10%, respectively.

Statistical Analysis
The ² test was applied for categorical variables. Patient survival was estimated by the Kaplan-Meier method from the date of diagnosis until death resulting from any cause or until the last patient follow-up. The survival curves were statistically compared by the log-rank test. A P of .05 was used as criterion for statistical significance. Proportional hazards regression analysis was used to identify the most significant independent prognostic variables on survival, and P values of less than .05 were considered statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ATM Deletion and Cytogenetic Features
A chromosome 11 deletion involving the 11q22-23 region, where the ATM gene is located, was seen by conventional chromosome analysis in two patients. In these patients, the 11q deletion was present in the stemline, in association with other anomalies. FISH detected a hemizygous ATM gene deletion (ATM+/-) (one fluorescent spot in 44% to 88% interphase cells) in these two patients and in 13 additional patients having two apparently normal copies of chromosome 11, giving an 11.1% incidence (15 of 135 patients) for this anomaly. Because all the samples consisted of more than 90% lymphoma cells, the presence of 70% cells with ATM deletion in the majority of cases argued in favor of the acquired nature of this chromosome lesion. We were able to rule out the presence of germline ATM deletion in six patients with more than 70% involved lymphoma cells by demonstrating the presence of two copies of the ATM gene in their normal peripheral-blood lymphocytes. Ten out of 15 patients had a complex karyotype and 11 out of 15 had more than 90% abnormal metaphases (AA karyotype status) (Table 1).

ATM Gene Deletion and BCL1 or TCL1 Rearrangement
Cohybridization of the BCL1 probe and of the ATM probe or of TCL1 probes and ATM probe in five normal controls showed that more than 90% of the cells had, as expected, two BCL1 or TCL1 red signals and two ATM green signals. Less than 1% of the cells had three red signals and two green signals (false BCL1/TCL1 rearrangement), less than 5% cells had two red and one green signal (false ATM deletion), and the remaining few cells had one red and two green signals or one red and one green signal (inefficient hybridization).

In four patients known to have t(11;14)/BCL1 rearrangement and ATM deletion in lymphoma cells, dual-color FISH revealed that the majority of cells had three red signals and one green signal (Table 3), indicative of BCL1 rearrangement and concomitant ATM gene deletion. However, in three of these patients, 8%, 12%, and 14% of all scorable cells displayed three red signals (BCL1 rearrangement) and two green signals (absence of ATM gene deletion) (Fig 1). In all four patients, the number of cells with only ATM deletion (two red/one green signal) was below the 5% cutoff point that was set for the recognition of ATM deletion. The majority of scorable cells showed three red signals and one green signal when hybridized to the TCL1/ATM probes, a finding indicative of the coexistence of TCL1 rearrangement and ATM deletion (Fig 1). The number of cells carrying only TCL1 rearrangement or only ATM deletion was below the sensitivity limit of this technique.

View larger version (20K): [in this window] [in a new window]   Fig 1. (A) One cell with BCL1 rearrangement and two copies of the ATM allele (three red and two green signals); (B) coexistence of TCL1 involvement (three red signals) and ATM deletion (one green signal) in all cells in a case of T-PLL with inv(14).

View larger version (14K): [in this window] [in a new window]   Fig 2. The survival of 15 patients with deletion of the ATM locus was shorter than the survival of 120 patients without deletion (P < .0001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The role of specific chromosome translocations in the development of distinct clinicopathologic types of NHL was firmly established.¹⁹ More recently, evidence was provided that unbalanced chromosome rearrangements, such as 1q aberrations, 6q deletion, 9p deletion, total or partial +12, and 17p13 deletion, may have clinicobiologic importance in several histologic subsets of lymphoid neoplasias.^14,20-23 Even though the role of some of these secondary chromosome lesions as prognostic markers was established, there is interstudy variability as to their impact on outcome, partly because of the paucity of cases studied and the heterogeneity of patient populations. The 11q22-23 deletion involving the ATM locus was associated with an aggressive form of B-CLL² and, very recently, with MCL,²⁴ but little is known about its potential significance in other B-cell neoplasias.

We identified 15 patients with an 11q/ATM deletion occurring in lymphoma cells among 135 cases of B-cell NHL and found an 11% incidence for this deletion, which showed no correlation with histologic grade and type. In most cases, no cytogenetically detectable 11q anomaly was present, suggesting that the more sensitive FISH technique is necessary for the demonstration of this chromosome lesion, which seems to be smaller than the detection limit of banding analysis. There is growing evidence of a role for the ATM gene in lymphomagenesis, suggesting that a strict correlation may exist between deletion at this locus and the lymphomatous phenotypic traits described in this report; however, we cannot exclude that the observed deletions at 11q22-23 could affect other genes mapping at this region, as suggested by studies in solid tumors.²⁵ In addition, because the analysis of the remaining allele was not undertaken, our findings do not provide direct evidence for an ATM loss-of-function mechanism as the basis for lymphomagenesis in our patients. In the article by Schaffner et al,¹¹ 23 patients with chronic lymphocytic leukemia/MCL with 11q- involving the ATM locus were studied by fine molecular methods, detecting mutations of the remaining allele in six patients. These data strongly support a pathogenetic role for ATM loss of function in sporadic lymphomas and suggest that future development of simple methods for the detection of ATM mutations will make it possible to analyze the correlation between ATM-inactivating mutations and clinical phenotype.

The model of lymphomagenesis in AT subjects postulates that the functional loss of ATM protein renders the T-lymphocyte precursors prone to develop illegitimate recombination of the T-cell receptor locus with other genes, including TCL1 and MTCP1.⁷ Cohybridization of the ATM probe with the BCL1 probe and TCL1 probe in dual-color experiments showed that deletion at the ATM locus occurred very early in the transformation process in those patients with T-PLL and inv(14), whereas it possibly was an additional change in three out of four patients with B-cell NHL and BCL1 rearrangement (Fig 1). The percentage of cells with ATM+/- in single color experiments was less than 80% in most of the remaining cases, providing further evidence for its secondary nature in B-cell NHL.

Interestingly, the AA karyotype status and complex karyotype were clearly associated with ATM+/- in lymphoma cells, suggesting that DNA loss at this locus may provide the neoplastic clone with in vitro growth advantage and may predispose to karyotype instability. The association of ATM+/- with complex karyotype did not seem to be simply a function of a nonspecific correlation possibly occurring between any chromosome lesion and karyotypes with many chromosomal rearrangements. Indeed, we have shown that 13q14 deletion in this series did not have a higher incidence in patients with complex karyotype, and we have previously shown that the occurrence of 17p- and +12 in MCL did not have a relationship with the degree of karyotype complexity.¹⁴

To better characterize the cytogenetic profile of B-cell NHL with deletion at the ATM locus, we focused our attention on total/partial +12, 13q14, and p53 deletions, which were shown by FISH to occur at a 46.6%, 26.6%, and 33.3% incidence, respectively, in ATM+/- cases (Table 1). A lower incidence for these anomalies was previously found in unselected B-cell NHL by molecular cytogenetic methods, which documented a 21% to 28% incidence for total/partial +12, a 20% incidence for 13q deletion, and a 18% incidence for 17p-/p53 deletion.^13,15,26 Thus, ATM+/- may have a positive correlation with some cytogenetic features, including the AA karyotype status, complex karyotype, and, possibly, total/partial +12 and 17p-. It is noteworthy that in previous studies some of these cytogenetic characteristics were shown to have an adverse impact on outcome^{13,20,21,27-30} and that, in this series, ATM+/- proved to be the strongest cytogenetic parameter influencing the 5-year survival rate.

Although some characteristics of this study (relatively small sample size and heterogeneity of histologic subsets) impose caution in the interpretation of the clinical correlations (Table 4), it is worth noting that many of the clinicobiologic characteristics, which were previously found to be prognostically significant in NHL,³¹ predicted for a shorter survival in this series and that, as in previous studies, complex karyotype was a negative prognostic factor.^13,21 Therefore, the finding of a strong predictive impact on survival of ATM locus deletion in the total series as well as in indolent and aggressive lymphomas is an important observation, especially when considering that there are few single chromosome rearrangements that have independent importance in risk assessment in NHL¹⁴ and that this cytogenetic lesion is easily detectable by an interphase FISH approach, a method which can be performed on fresh cells as well as in formalin-fixed samples.³² The possible role of deletion at the ATM locus as a negative prognostic factor in specific histologic subsets of NHL might be assessed in prospective cytogenetic studies including a larger number of patients.

	ACKNOWLEDGMENTS

 
Supported by Ministero dell’Università e della Ricerca Scientifica e Technologica fondi ex 40% and 60%, by Biomed-1 European Union Concerted Action: CT 94–1703, by the Associazione Italiana per la Ricerca sul Cancro, and European Commission grant QLRT-1999–00786.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 17, 1999; accepted March 2, 2000.

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